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  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
  • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
  • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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  • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
  • B01J23/46—Ruthenium, rhodium, osmium or iridium
  • B01J23/462—Ruthenium
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  • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
  • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
  • B01J23/54—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals combined with metals, oxides or hydroxides provided for in groups B01J23/02 - B01J23/36
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  • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
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  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
  • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
  • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/41—Preparation of salts of carboxylic acids
• • C—CHEMISTRY; METALLURGY
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  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/41—Preparation of salts of carboxylic acids
  • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

• the present invention relates to synthesis methods for a-amino acids and a-amino acid derivatives, from a-, b-dihydroxy carbonyl starting compounds, including a-, b-dihydroxy carboxylic acids and carboxylates such as products obtained from glucose.
• Amino acids are the building blocks for protein synthesis and have a number of commercial uses, particularly as nutritional supplements.
• One important application resides in the use of amino acids as additives of animal feeds. This is due to the low levels, or in some cases the complete lack, of certain essential amino acids in the primary constituents of such feeds, such as soybeans.
• Amino acids are currently indispensable ingredients for improving the efficiency in the natural (biological) production of animal protein (e.g., in the form of meat and milk), and for generally increasing the overall supply of such high value protein.
• aspects of the invention are associated with the discovery of amino acid synthesis methods that can utilize substrates such as gluconic acid and glucaric acid, which are readily derived, for example from the oxidation of glucose.
• substrates such as gluconic acid and glucaric acid
• they may potentially exhibit greater stability compared to their precursor aldehydes (e.g., glucose). Under high temperature reaction conditions, this stability can lead to increased reaction selectivity and yield along a desired reaction sequence leading to the production of one or more defined amino acids. Product losses due to undesired side reactions are thereby reduced.
• FIG. 6 Further aspects relate to optional synthesis pathways that utilize a cracking step, resulting in an a-amino acid having a lower number of carbon atoms, relative to the substrate and/or precursor of this substrate.
• This cracking can be regulated by the use of a cracking catalyst or promoter, as well as reaction conditions, as described herein.
• the extent of cracking can thereby determine the relative yields of (i) same carbon atom-numbered a-amino acids relative to the substrate (i.e.. obtained without intermediate cracking), and (ii) lower carbon atom-numbered a-amino acids relative to the substrate (i.e.. obtained with intermediate cracking).
• More particular aspects relate to the discovery of synthesis pathways, or individual reaction steps of such pathways, which may be performed non-enzymatically, meaning without the use of an enzyme (e.g.. a polypeptide) in the reaction mixture.
• an enzyme e.g.. a polypeptide
• advantages reside in terms of allowing a wider range of possible reaction conditions, such as conditions of temperature and/or pH that would be detrimental to biological agents (e.g., would denature proteins including enzymes) but that nonetheless allow high productivities of a desired intermediate and/or end product.
• At least one of the synthesis steps described herein of (i) dehydrating the starting compound to form the dicarbonyl intermediate, (ii) cracking the dicarbonyl intermediate to form the cracked dicarbonyl intermediate, (iii) reductively aminating the dicarbonyl intermediate or the cracked dicarbonyl intermediate to produce the a-amino acid or a-amino acid derivative is a non-enzymatic reaction step (i.e. is not catalyzed using an enzyme).
• at least two of (i), (ii), and (iii) are non-enzymatic reaction steps, and more preferably all of (i), (ii), and (iii) are non-enzymatic reaction steps.
• representative methods comprise synthesizing 2-amino-3- deoxygluconic acid (2-amino-4,5,6-trihydroxyhexanoic acid) from gluconic acid or glucaric acid, synthesizing aspartic acid from tartaric acid, or synthesizing homoserine from erythronic acid.
• representative methods comprise synthesizing alanine from 4- , 5-, or 6-carbon atom-numbered substrates, for example gluconic acid or glucaric acid.
• the alanine may be obtained from a reaction pathway involving a variety of possible starting compounds, with cracking to form a pyruvic acid intermediate.
• this starting compound namely an a-, b-dihydroxy carbonyl compound, /. e..
• a general class of compounds that embraces a-, b-dihydroxy carboxylic acids and carboxylates is dehydrated to form a dicarbonyl intermediate by transformation of the a-hydroxy group to a second carbonyl group (adj acent a carbonyl group of the starting compound) and removal of the b-hydroxy group.
• the dicarbonyl intermediate is optionally cracked to form a second, in this case cracked, dicarbonyl intermediate having fewer carbon atoms relative to the dicarbonyl intermediate but preserving the first and second carbonyl groups.
• Either or both of the dicarbonyl intermediate and the cracked dicarbonyl intermediate are aminated (e.g , with gaseous ammonia, NEE, or aqueous ammonia, NH4OH), such that the second carbonyl group of the intermediate and/or cracked intermediate is converted to an amino (-NEE) group, to produce the a-amino acid(s).
• aminated e.g , with gaseous ammonia, NEE, or aqueous ammonia, NH4OH
• aminating agents such as substituted amines (e.g., alkylamines or dialkylamines), may likewise be used to alternatively convert the second carbonyl group to the corresponding, substituted amino group (e.g , alkylamino or dialky lamino), and thereby produce the corresponding a-amino acid derivative(s).
• substituted amines e.g., alkylamines or dialkylamines
• substituted amino group e.g , alkylamino or dialky lamino
• Figure 1 illustrates a general reaction mechanism, comprising steps for synthesizing a- amino acids according to synthesis methods described herein.
• Figure 2 illustrates a specific reaction mechanism, according to which gluconic acid is the starting material or substrate, with specific byproducts also shown.
• the term“substrate,” or alternatively,“starting compound,” refers to the initial compound that is subjected to one or preferably a series of conversion steps, such as “dehydrating,” optional“cracking,” and“aminating” conversion steps, to yield an a-amino acid or a-amino acid derivative. These conversion steps do not preclude the use of prior conversion steps, such as under the same reaction conditions (e.g., in the same reactor) or under different reaction conditions (e.g., in a separate reactor), as used to produce the a-amino acid or a-amino acid derivative.
• Such prior conversion steps can include the conversion of a readily available precursor, such as glucose, to gluconic acid or glucaric acid as the starting compound, such as by oxidation.
• a step of“producing the a-amino acid or a-amino acid derivative” does not preclude the use of subsequent conversion steps, such as under the same reaction conditions (e.g., in the same reactor) or under different reaction conditions (e.g., in a separate reactor), as used to produce the a-amino acid or a-amino acid derivative, to obtain one or more other desired end products.
• the a-amino acid produced by the series of conversion steps may be homoserine (having an a-amino acid side chain of-CTFEOH).
• the desired end product methionine (having an a-amino acid side chain of -C2H5SCH3) may be obtained, for example, by the subsequent chemical conversion of the homoserine in the presence of a mercaptan compound (e.g., methylmercaptan). Methods for this conversion also include known routes based on fermentation.
• a mercaptan compound e.g., methylmercaptan
• a-amino acid derivative of an a-amino acid refers to any chemical compound wherein the carboxylic acid substituent of that a-amino acid may be converted to, or has the corresponding chemical structure of, an ester, aldehyde or ketone and/or the primary amine substituent of that a-amino acid is converted to, or has the corresponding chemical structure of, a secondary or tertiary amine or is replaced by another substituent which can include hydroxy, halogen among others.
• mol-% and“wt-%” are used to designate amounts or concentrations in terms of percent by mole and percent by weight, respectively.
• Product yields given in terms of “mol-%” refer to the moles of a given product (e.g . , an a-amino acid such as alanine) obtained, based on the moles of substrate used (introduced or fed to the reactor).
• alkyl when used alone or in combination with other moieties, for example, when used in combination in “alkoxy,” “alkoxyalkyl,” “hydroxyalkyl,” “carboxyalkyl,” “alkanoyl,” and“alkanoyl alkyl,” represents a hydrocarbon moiety that is derived from an alkane.
• “alkyl” therefore includes“methyl” (CH 3 -),“ethyl” (C 2 H 5 -), etc.
• the alkyl portion of the moiety“alkoxy” is bonded at an end of the moiety to the rest of the molecule, through an intervening oxygen linkage, -0-, such as in the case of“methoxy” (CH 3 -O-),“ethoxy” (C 2 H 5 -O-), etc., which terms are encompassed by “alkoxy.”
• the term“hydroxy” represents the moiety -OH
• the term“hydroxyalkyl” represents hydroxy bonded at the end of the moiety to the rest of the molecule, through an intervening divalent alkyl portion, such as in the case of “hydroxymethyl” (HO-CH 2 -),“hydroxy ethyl” (HO-C 2 H 5 -), etc., which terms are encompassed by“hydroxyalkyl.”
• the term“alkoxyalkyl” includes both
• “alkoxyalkyl” encompasses “methoxymethyl” (CH 3 -O-CH 2 -), “methoxy ethyl” (CH 3 -O-C 2 H 4 -), “ethoxymethyl” (C 2 H 5 -O-CH 2 -), “ethoxyethyl” (C 2 H 5 -O-C 2 H 4 -), etc.
• alkanoylalkyl includes both a terminal alkanoyl portion (i.e..
• a terminal alkyl portion its terminal carbon atom may be substituted with two CTT substituents, to yield a terminal isopropyl moiety, or may be substituted with three CTT substituents, to yield a terminal t-butyl moiety.
• an intervening alkyl portion, or an intervening carbon atom of a terminal alkyl portion one or two hydrogen substituents at carbon-hydrogen bonds of an alkylene carbon atom may be substituted with - CTT substituents to yield the corresponding methyl-substituted or dimethyl-substituted derivatives.
• phrase“having from 1 to 5 carbon atoms,” and other phrases defining the number of alkyl carbon atoms refer to a backbone number of alkyl carbon atoms that may be further substituted with -CH3 substituents or other substituents, according to the specific definitions given.
• Carboxylic acid compounds including amino acids, include their corresponding salt forms.
• the salt form is normally used in aqueous solution for carrying out the synthesis methods described herein.
• Corresponding salt forms of carboxylic acid include, for example, salts of alkali metals (e.g., the sodium salt form), salts of alkaline earth metals (e.g, the calcium salt form), and ammonium salts.
• compounds such as“gluconic acid,”“glucaric acid,” “2-amino-3-deoxygluconic acid” (or “2-amino-4,5,6-trihydroxyhexanoic acid”), “aspartic acid,”“tartaric acid,”“homoserine,”“lactic acid,” etc. are meant to encompass salt forms of “gluconate,” “glucarate,” “2-amino-3-deoxy gluconate” (or “2-amino-4,5,6- trihydroxyhexanoate”),“aspartate,”“tartarate,”“homoserinate,”“lactate,” etc.
• the structure of alanine for example, when shown with these groups being un-ionized, is meant to encompass structures with one or both of these groups being ionized, with un-ionized and ionized amino and carboxyl groups of the equivalent structures of this compound shown below:
• “gluconic acid” is intended to encompass“gluconic acid and stereoisomers thereof,” as is intended with respect to other compounds designating a specific stereochemistry.
• Generic and specific compounds described herein may be used or obtained in the form of pure or purified (enriched) optical isomers or otherwise in the form of racemic mixtures thereof.
• optically active substrates or starting compounds will result in the formation of optically active products, including a-amino acids and a-amino acid derivatives, using the synthesis methods described herein, as would be appreciated by those having skill in the art, combined with knowledge from the present disclosure.
• the purification of a particular optical isomer, or enrichment in one optical isomer relative to another can be obtained, for example, by the formation of diastereomeric salts through treatment with an optically active acid or base.
• appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
• appropriate bases are plant-derived chiral alkaloids.
• the mixtures of diastereomers are then separated by crystallization, followed by liberation of the optically active bases or acids from these salts.
• a different process for separation of optical isomers involves the use of a chiral chromatography column chosen to maximize the separation of the enantiomers.
• Still another available method involves synthesis of covalent diastereomeric molecules by reaction with an optically pure acid in an activated form or an optically pure isocyanate.
• the synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to yield the enantiomerically pure compound.
• FIG. 1 A general reaction mechanism for synthesizing a-amino acids is illustrated in FIG. 1.
• a compound of general Formula I is a starting compound that is broadly an a-, b- dihydroxy carbonyl compound, which encompasses a preferred class of compounds, namely a-, b-dihydroxy carboxylic acid or carboxylate when R 1 is hydroxy (-OH) to provide a terminal carboxyl group on the left-hand side of the illustrated compound.
• a first step of dehydration causes removal of the b-hydroxy group, together with formation of a site of unsaturation, /. e.. a carbon-carbon double bond between the a-carbon atom and the b-carbon atom.
• the resulting ethylenically unsaturated, dehydrated compound, shown as compound A tends to maintain tautomeric equilibrium with the dicarbonyl intermediate shown as having general Formula IIA.
• the dehydrating step may therefore comprise forming water from a combination of the b-hydroxy group and hydrogen of the a-hydroxy group, in a starting compound or substrate of general Formula I.
• Animation of this dicarbonyl intermediate with an animating agent, or reductive aminating agent, of the formula NHR 3’ R 3" , as shown, can produce an a-amino acid or a-amino acid derivative having the general Formula IIIA
• FIG.1 which may be an a-amino acid, for example in the case of R 1 being hydroxy (-OH) and the aminating agent being gaseous or aqueous ammonia (ammonium hydroxide), such that R 3’ and R 3" are each hydrogen substituents.
• the compound above may be a particular a-amino acid derivative, having at least a derivatized amino group, in the case of other types of aminating agents, such as monoalkyl or dialkyl amines.
• methylamine as an aminating agent can result in the corresponding methylamino acid derivative, in which case one of R 3’ and R 3" may be a hydrogen substituent and the other a methyl substituent, and methylethylamine as an aminating agent can result in the corresponding methyl, ethyl diamino acid derivative, in which case one of R 3’ and R 3” may be a methyl substituent and the other an ethyl substituent.
• R 3’ and R 3 may be a hydrogen substituent and the other a methyl substituent
• methylethylamine as an aminating agent can result in the corresponding methyl, ethyl diamino acid derivative, in which case one of R 3’ and R 3” may be a methyl substituent and the other an ethyl substituent.
• the dicarbonyl intermediate compound of general Formula IIA may optionally undergo cracking to form the cracked dicarbonyl intermediate of general Formula IIB.
• the moiety represented by R 2B in the cracked dicarbonyl intermediate of general Formula IIB has fewer carbon atoms relative to the moiety represented by R 2A in the dicarbonyl intermediate of general Formula IIA.
• the cracked dicarbonyl intermediate overall has fewer carbon atoms relative to the dicarbonyl intermediate.
• Amination of the cracked dicarbonyl intermediate can then produce an a-amino acid or a-amino acid derivative having the general Formula IIIB
• this second cracked species may have the structure according to compound B, as shown and having an aldehyde group.
• this second cracked species may include other functional groups, such as a carboxylic acid functional group, as the moiety represented by R 2C , or otherwise included in a terminal portion of this moiety, which is bonded to the aldehyde functional group.
• Such a second cracked species may result, for example, when the moiety represented by R 2A in the dicarbonyl intermediate of general Formula IIA is bonded through a hydroxy-substituted carbon atom.
• the second cracked species of compound B may result in the case of R 2A , or at least a terminal portion of R 2A , representing a moiety of
• the cracked dicarbonyl intermediate will have fewer carbon atoms, relative to both the dicarbonyl intermediate and the substrate.
• the cracked dicarbonyl intermediate may then become aminated, whereas further conversions of the second cracked species (e.g, by amination and/or hydrogenation) may form other desirable compounds, for example as described with respect to the more particular embodiment shown in FIG. 2.
• the moiety represented by R 2C in compound B may have one fewer carbon atom, relative to the moiety represented by R 2A , and compound B may represent a corresponding aldehyde formed from R 2A and having the same number of carbon atoms as R 2A .
• the cracked dicarbonyl intermediate may be pyruvic acid, which may become aminated to alanine.
• a synthesis route to alanine, through cracking of the dicarbonyl intermediate to form pyruvic acid can be carried out using a variety of a-, b- dihydroxy carbonyl compounds, including a-, b-dihydroxy carboxylic acids and carboxylates having at least four carbon atoms, as substrates.
• a 3 carbon atom-numbered a-amino acid such as alanine
• a 3 carbon atom-numbered a-amino acid may be produced from available 4-, 5-, or 6-carbon atom-numbered a-, b- dihydroxy carboxylic acids and carboxylates as starting compounds, such as erythronic acid (or 2,3,4-trihydroxybutanoic acid generally); 2,3-dihydroxy-4-oxobutanoic acid; tartaric acid; 2,3,4,5-tetrahydroxypentanoic acid; 2,3,4-trihydroxy-5-oxopentanoic acid; 2,3,4- trihydroxypentanedioic acid; gluconic acid (or 2,3,4,5,6-pentahydroxyhexanoic acid generally); 2,3,4,5-tetrahydroxy-6-oxohexanoic acid, and glucaric acid (or 2, 3,4,5- tetrahydroxyhexanedioic acid generally).
• a- amino acids or their derivatives having different numbers of carbon atoms, may be formed from a combination of both synthesis via a di carbonyl intermediate and synthesis via a cracked dicarbonyl intermediate, with relative yields of the different a-amino acids or their derivatives being regulated.
• all or substantially all (e.g., greater than 95 mol-%) of the a-amino acid or a-amino acid derivative produced according to the synthesis method may be via animation of the dicarbonyl intermediate of general Formula IIA, in which case this a-amino acid or a-amino acid derivative may have the same number of carbon atoms as the dicarbonyl intermediate, as well as the substrate.
• R 1 may be alkyl (e.g., having from 1 to 3 alkyl carbon atoms) and may result in a terminal ketone functional group in the respective compounds; R 1 may be alkoxy (e.g., having from 1 to 3 alkyl carbon atoms) and may result in a terminal ester functional group in the respective compounds; or R 1 may be hydroxy and may result in a terminal carboxyl functional group in the respective compounds.
• R 1 is hydroxy, whereby the starting compound and the dicarbonyl intermediate are carboxylic acids.
• the starting compound, the dicarbonyl intermediate, and the a-amino acid or a-amino acid derivative may be in the form of (e.g., present in the reaction mixture as) carboxylates, meaning compounds comprising a carboxylate anion and possibly present in salt form in an aqueous reaction mixture (e.g., in their corresponding ammonium salt form) that is used to carry out synthesis methods described herein.
• R 2A may selected from the group consisting of a hydrogen substituent, alkyl, alkoxy, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, and alkanoylalkyl, wherein alkyl and the alkyl portions of alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, and alkanoylalkyl have from 1 to 3 carbon atoms, optionally substituted with one or more of -OH and/or one or more of -CH3.
• R 2A may be a hydrogen substituent, alkyl, carboxy, carboxyalkyl, alkanoyl, or alkanoylalkyl, wherein alkyl and the alkyl portions of carboxyalkyl, alkanoyl, and alkanoylalkyl have from 1 to 3 carbons atoms, optionally substituted with one or more of -OH.
• Particular substrates having from 3-6 carbon atoms include 2,3-dihydroxy propanoic acid; erythronic acid (or 2,3,4-trihydroxybutanoic acid generally); 2,3-dihydroxy-4-oxobutanoic acid; tartaric acid; 2,3,4,5-tetrahydroxypentanoic acid; 2,3,4-trihydroxy-5-oxopentanoic acid; 2,3,4-trihydroxypentanedioic acid; gluconic acid (or 2,3,4,5,6-pentahydroxyhexanoic acid generally); 2,3,4,5-tetrahydroxy-6-oxohexanoic acid, and glucaric acid (or 2,3,4,5-tetrahydroxyhexanedioic acid generally).
• R 2A is a hydrogen substituent
• cracking to form a cracked dicarbonyl intermediate of general Formula IIB cannot occur.
• an a-amino acid or a-amino acid derivative may be produced from the dicarbonyl intermediate of general Formula IIA, for example in the production of alanine from 2-,3-dihydroxy propanoic acid, in the absence of cracking.
• R 2B may selected from the group consisting of a hydrogen substituent, alkyl, alkoxy, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, and alkanoylalkyl, wherein alkyl and the alkyl portions of alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, and alkanoylalkyl have from 1 to 3 carbon atoms, optionally substituted with one or more of -OH and/or one or more of -CH 3 .
• R 2B may be a hydrogen substituent, alkyl, carboxy, carboxyalkyl, alkanoyl, or alkanoylalkyl, wherein alkyl and the alkyl portions of carboxyalkyl, alkanoyl, and alkanoylalkyl have 1 or 2 carbons atoms, optionally substituted with one or more of -OH.
• R 2B may be a hydrogen substituent or alkyl having from 1 to 3 carbon atoms, optionally substituted with one or more of -OH.
• the cracked dicarbonyl intermediate is pyruvic acid that may become aminated to form alanine, potentially from a variety of possible a-, b-hydroxy carboxylate substrates, as described above.
• the second cracked species of compound B may result in the case of R 2A , or at least a terminal portion of R 2A , representing a moiety of Accordingly, R 2C in compounds having the general formula given for compound B may represent moieties as defined above with respect to R 2A , but having at least one fewer carbon atom.
• R 2C may selected from the group consisting of a hydrogen substituent, alkyl, alkoxy, hydroxy, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, and alkanoylalkyl, wherein alkyl and the alkyl portions of alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, and alkanoylalkyl have one or two carbon atoms, optionally substituted with one or more of -OH and/or one or more of -CH3.
• R 2C may be a hydrogen substituent or alkyl having one or two carbon atoms, optionally substituted with one or more of -OH.
• R 3’ and R 3” are independently a hydrogen substituent or alkyl having from 1 to 3 carbon atoms. More preferably, R 3’ and R 3" are independently a hydrogen substituent, methyl, or ethyl. Still more preferably R 3’ and R 3” are both a hydrogen substituent.
• a typical reaction environment associated with the synthesis of an a-amino acid or a- amino acid derivative, according to methods described herein, includes an elevated hydrogen partial pressure, such as a hydrogen partial pressure of at least 3 megapascals (MPa) (435 psi), optionally in combination with a hydrogenation catalyst.
• a hydrogen partial pressure such as a hydrogen partial pressure of at least 3 megapascals (MPa) (435 psi)
• MPa megapascals
• the terminal aldehyde group in the second cracked species of compound B may be converted to a terminal alcohol or hydroxy (-OH) group.
• FIG. 2 illustrates the synthesis method presented in FIG. 1, using gluconic acid (or generally 2,3,4,5,6-pentahydroxyhexanoic acid) as a starting compound, or compound of Formula I, in which R 2A represents the moiety
• the dicarbonyl intermediate of Formula IIA is 2-keto-3-deoxygluconic acid (2-keto-4,5,6-trihydroxyhexanoic acid), as shown.
• This dicarbonyl intermediate can then undergo amination with gaseous or aqueous ammonia to yield an a-amino acid, having the same number of carbon atoms relative to the starting compound.
• this a-amino acid is 2-amino-3-deoxy gluconic acid (2-amino-4,5,6-trihydroxyhexanoic acid), which is shown as the compound having Formula IIIA.
• the dicarbonyl intermediate can undergo cracking to yield a cracked dicarbonyl intermediate of Formula IIB, which in the embodiment illustrated in FIG. 2 is pyruvic acid. Amination of this cracked dicarbonyl intermediate then provides a pathway to a different a-amino acid, having fewer carbon atoms relative to the starting compound. In this case, this different a-amino acid is alanine, shown as the compound having Formula IIIB.
• cracking to form pyruvic acid additionally forms a second cracked species of compound B, in this case is glyceraldehyde, according to which R 2C in the general formula for this compound as shown in FIG. 1, is a moiety of
• glyceraldehyde the second cracked species of compound B, can undergo further reactions, such as those involving a 1, 2-hydride shift or a hydride transfer (Cannizzaro reaction) to cause its conversion to lactic acid, as shown in FIG. 2.
• glyceraldehyde can combine with alanine to form an alanine/glyceraldehyde dimer, as also shown.
• alanine and lactic acid may be produced in a combined molar amount that exceeds a net molar amount of glyceraldehyde produced, despite the fact that the cracking reaction may yield equimolar amounts of pyruvic acid (which may become aminated to produce alanine or hydrogenated to produce lactic acid) and glyceraldehyde.
• the ratio of the combined molar amount of alanine and lactic acid to the net molar amount of glyceraldehyde e.g, in the reaction mixture after completion of a synthesis method
• This excess may result, at least in part, due to the conversion of glyceraldehyde to lactic acid.
• Representative synthesis methods therefore comprise reacting an a-, b-dihydroxy carboxylic acid or carboxylate starting compound in a reaction mixture, to form an a-amino acid or a-amino acid derivative having the same number of carbon atoms, relative to the starting compound, and/or to form an a-amino acid or a-amino acid derivative having fewer carbon atoms, relative to the starting compound.
• the reaction mixture preferably comprises a cracking catalyst or promoter of the reaction step shown as“optional cracking” in FIGS. 1 and 2.
• Preferred cracking catalysts comprise one or more cracking active metals, such as tungsten, molybdenum, and/or vanadium, which may be present in the form of corresponding salts in the reaction mixture, such as tungstate, molybdate, or vanadate salts, which include a metatungstate salt, a paratungstate salt, a metamolybdate salt, a paramolybdate salt, a metavanadate salt, or a paravanadate salt.
• Representative tungstate salts are salts of Group 1 (alkali) metals or Group 2 (alkaline earth) metals, as well as ammonium salts. Ammonium metatungstate and ammonium paratungstate salts are representative.
• a cracking catalyst e.g.
• ammonium metatungstate may be present in the reaction mixture in an amount of from 0.1 mol-% to 30 mol-%, from 0.5 mol-% to 10 mol-%, or from 1 mol-% to 5 mol-%, relative to the number of moles of substrate, for example according to the initial reactor loading composition in the case of a batchwise reaction or according to a steady-state composition in the case of a continuous reaction.
• the cracking catalyst may also, or may alternatively, be present in the reaction mixture in an amount such that the moles of cracking active metal (e.g., tungsten, molybdenum, or vanadium) may represent from 6 mol-% to 50 mol-%, or from 10 mol-% to 35 mol-%, relative to the number of moles of substrate.
• Other cracking catalysts can include solid acids and/or Lewis acids (e.g., organometallic compounds, including organotin compounds).
• particular methods comprise synthesizing alanine from an a-, b-dihydroxy carboxylate starting compound having greater than 3 carbon atoms, such as a salt of gluconate (or 2,3,4,5,6-pentahydroxyhexanoate generally); 2, 3,4,5- tetrahydroxy-6-oxohexanoate; glucarate (or 2,3,4,5-tetrahydroxyhexanedioate generally); 2,3,4,5-tetrahydroxypentanoate; 2,3,4-trihydroxy-5-oxopentanoate; 2,3,4- trihydroxypentanedioate; erythronate (or 2,3,4-trihydroxybutanoate generally); 2,3-dihydroxy- 4-oxobutanoate; or tartarate.
• a salt of gluconate or 2,3,4,5,6-pentahydroxyhexanoate generally
• 2, 3,4,5- tetrahydroxy-6-oxohexanoate glucarate (or 2,3,4,5-t
• such methods comprise dehydrating this starting compound to form a dicarbonyl intermediate by transformation of the alpha hydroxy group to a second carbonyl group and removal of the beta hydroxy group, and cracking this dicarbonyl intermediate to form pyruvate.
• the pyruvate is then aminated to produce the alanine.
• the cracking catalyst can be used to regulate the relative yields of (i) a-amino acids and/or a-amino acid derivatives having the same number of carbon atoms relative to the substrate and obtained from a synthesis pathway that does not include cracking and (ii) a-amino acids and/or a-amino acid derivatives having fewer carbon atoms relative to the substrate and obtained from a synthesis pathway that includes cracking.
• the yield(s) of a-amino acids and/or a-amino acid derivatives according to (i) above may account for at least 85 mol-%, or even at least 95 mol-%, of the molar yield(s) of all a-amino acids and/or a-amino acid derivatives produced.
• the molar yield(s) of a-amino acids and/or a-amino acid derivatives according to (ii) above may account for at least 50 mol-% (e.g, from 50 mol-% to 95 mol-%), or at least 75 mol-% (e.g, from 70 mol-% to 90 mol-%), of the molar yield(s) of all a-amino acids and/or a-amino acid derivatives produced.
• the total yield(s) of a-amino acids and/or a-amino acid derivatives according to (i) above and/or the total yield(s) of a-amino acids and/or a-amino acid derivatives according to (ii) above, based on the theoretical yields proceeding through the respective non-cracking pathway (i) or optional cracking pathway (ii), may be generally at least 25 mol-% (e.g, from 25 mol-% to 90 mol-%), typically at least 35 mol-% (e.g, from 35 mol- % to 80 mol-%), and often at least 50 mol-% (e.g, from 50 mol-% to 75 mol-%).
• yields can apply, for example, to any of the a-amino acids and/or a-amino acid derivatives according to general Formulas IIIA and IIIB described herein, including the specific a-amino acids and/or a-amino acid derivatives described herein (e.g., alanine) as products of the synthesis.
• the reaction mixture which is preferably an aqueous reaction mixture, may further comprise an aminating agent such as gaseous or aqueous ammonia (ammonium hydroxide) as described above, and/or otherwise possibly an alkylated amine such as a compound of the formula NHR 3’ R 3" , wherein R 3’ and R 3 are as defined herein, e.g., with respect to compounds according to Formula IIIA and IIIB.
• an aminating agent such as gaseous or aqueous ammonia (ammonium hydroxide) as described above, and/or otherwise possibly an alkylated amine such as a compound of the formula NHR 3’ R 3" , wherein R 3’ and R 3 are as defined herein, e.g., with respect to compounds according to Formula IIIA and IIIB.
• ammonium salts such as ammonium halides, may also be used in place of, or in combination with, ammonium hydroxide.
• ammonium salts e.g., ammonium hydroxide and/or ammonium chloride
• concentration, or combined concentration from 10 wt-% to 50 wt-%, or from 15 wt-% to 35 wt-%.
• amount of solution comprising such ammonium salt(s) is at least sufficient to solubilize the substrate, cracking catalyst (if used), and any additives, in an aqueous solution as the reaction mixture.
• the reaction mixture may further comprise a hydrogenation catalyst, such as solid (heterogeneous) catalyst.
• a representative hydrogenation catalyst may comprise one or more hydrogenation active metals selected from Groups 8-11 of the Periodic Table, such as, for example, ruthenium (Ru), cobalt (Co), nickel (Ni), platinum (Pt), palladium (Pd), or gold (Au).
• a preferred hydrogenation active metal is ruthenium.
• the catalyst may further comprise a solid support of the hydrogenation active metal(s), with the metals being dispersed on the solid support according to a distribution, for example preferentially near the outer surface of the solid support or otherwise substantially uniformly throughout a porous solid support, depending on the particular catalyst preparation technique used (e.g., evaporative impregnation of a solution of the hydrogenation active metal).
• the hydrogenation active metal, or such metals in combination is/are present in an amount from 1 wt-% to 15 wt-%, or from 2 wt-% to 10 wt- %, based on the total weight of the hydrogenation catalyst.
• the hydrogenation active metal(s) may also, or may alternatively, be present in the reaction mixture in an amount such that the moles of hydrogenation active metal(s) (e.g., ruthenium) represent from 1 mol-% to 20 mol-%, or from 2 mol-% to 10 mol-%, relative to the number of moles of substrate, for example according to the initial reactor loading composition in the case of a batchwise reaction or according to steady-state composition in the case of a continuous reaction.
• the solid support is preferably refractory in the reaction mixture and under the synthesis reaction conditions described herein.
• Representative solid supports comprise one or more metal oxides, such as aluminum oxide (alumina), silicon oxide (silica), titanium oxide (titania), zirconium oxide (zirconia), magnesium oxide (magnesia), strontium oxide (strontia), etc.
• a preferred solid support is carbon.
• the hydrogenation catalyst comprises ruthenium on a carbon support, with the ruthenium being present in an amount within a range given above, based on total catalyst weight and/or within a range given above, relative to the number of moles of substrate.
• Reaction conditions under which the reaction mixture is maintained during the synthesis of the a-amino acid and/or a-amino acid derivative, include an elevated pressure and hydrogen partial pressure.
• Representative absolute reactor pressures are in the range generally from 2.07 MPa (300 psi) to 24.1 MPa (3500 psi), typically from 3.45 MPa (500 psi) to 20.7 MPa (3000 psi), and often from 10.3 MPa (1500 psi) to 17.2 MPa (2500 psi).
• the reactor pressure may be generated predominantly or substantially from hydrogen, such that these ranges of total pressure may also correspond to ranges of hydrogen partial pressure.
• the presence of gaseous ammonia or other aminating agent, as well as other gaseous species vaporized from the reaction mixture, may result in the hydrogen partial pressure being reduced relative to these total pressures, such that, for example, the hydrogen partial pressure may range generally from 1.38 MPa (200 psi) to 22.4 MPa (3250 psi), typically from 2.41 MPa (350 psi) to 19.0 MPa (2750 psi), and often from 8.62 MPa (1250 psi) to 15.5 MPa (2250 psi).
• reaction conditions include a temperature from l00°C to 350°C, and preferably from l30°C to 230°C.
• the reaction time, /. e.. time at which the reaction mixture is maintained under conditions of pressure and temperature at any target values or target sub-ranges within any of the ranges of pressure and temperature given above e.g, a target, total pressure value of 13.8 MPa (2000 psi) and a target temperature of l60°C
• a target, total pressure value of 13.8 MPa (2000 psi) and a target temperature of l60°C is from 0.5 hours to 24 hours, and preferably from 1 hour to 5 hours, in the case of a batch wise reaction.
• these reaction times correspond to reactor residence times.
• Continuous operation may be performed, for example, under the conditions of pressure and temperature described above, with continuous feeding of the substrate, aminating agent, and hydrogen, and continuous withdrawal of the reaction mixture comprising the a-amino acid or a-amino acid derivative.
• Continuous operation may further include the continuous purification of the a-amino acid or a-amino acid derivative, the continuous separation of process streams comprising unconverted gaseous and/or liquid products, and/or the continuous recycle of one or more of such process streams back to the reaction mixture, maintained in the synthesis reactor.
• the yields of the a-amino acid or a-amino acid derivative, as described above will correspond to the“once-through” or“per-pass” yield, with higher overall yields being possible due to the recycle.
• Parr reactor was pressurized to below the target pressure of 13.8 MPa (2000 psi), and the reaction mixture was heated to a target temperature of 200°C. Upon achieving this target (reaction) temperature, the pressure was increased to the target value, marking the starting point for the reaction time of 2 hours. The reaction mixture was allowed to stir under these conditions of pressure and temperature for this reaction time, after which the reaction mixture was cooled to below 80°C and depressurized. The reaction mixture was then filtered to remove solids, and vial samples were submitted for composition analysis by gas chromatography-mass spectrometry (GC-MS).
• GC-MS gas chromatography-mass spectrometry
• a sixth experiment was conducted according to the procedures described in Example 1, except that the reaction temperature was l80°C, and 4.64 grams of a solid, carbon-supported ruthenium hydrogenation catalyst (5 wt-% Ru, BASF) was used, providing 2.5 mol-% Ru, relative to the gluconic acid substrate (assuming 50 wt-% moisture content of the catalyst). Also, an additive of 0.25 grams of ammonium acetate, or 7 mol-% relative to the substrate, was included in the initial reaction mixture.
• aspects of the invention relate to the use of synthesis methods described herein to produce a-amino acids and/or a-amino acids derivatives from readily available, or easily derived, substrates.
• the methods may advantageously address various shortcomings of conventional methods.
• Those having skill in the art, with the knowledge gained from the present disclosure, will recognize that various changes can be made to these processes in attaining these and other advantages, without departing from the scope of the present disclosure.
• the features of the disclosure are susceptible to modifications and/or substitutions without departing from the scope of this disclosure.
• the specific embodiments illustrated and described herein are for illustrative purposes only, and not limiting of the invention as set forth in the appended claims.

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